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THE ROLES OF TRPM8 IN COLD SENSATION: THE SIX SIDES OF TRPM8
by
Wendy Michelle Knowlton
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
August 2012
Copyright 2012 Wendy Michelle Knowlton

Our ability to detect temperatures is conferred by thermally-activated sensory neurons of the peripheral nervous system which innervate the skin, with cell bodies located in the dorsal root and trigeminal ganglia. These thermosensitive neurons express thermally sensitive ion channels of the transient receptor potential (TRP) family, including TRPV1, which responds to hot temperatures as well as the ‘hot’ ingredient in chili peppers, capsaicin, and TRPM8, which responds to cold temperatures and the ‘cool’ ingredient in mint, menthol. Beyond thermosensation, these channels have been implicated in a variety of functions including pain, thermoregulation, pain relief, and itch. ❧ Here we examine the roles of the cold-sensitive channel TRPM8 in sensory behavioral responses. We use three main approaches in this study: the disruption of the Trpm8 gene in mice, the ablation of TRPM8-expressing cells in adulthood using BAC transgenesis and the simian diphtheria toxin receptor transgene, and administration of the potent TRPM8 antagonist PBMC. ❧ We found six behaviors are affected by TRPM8 expression using one or more of these methods. These behaviors fall into two general categories: active, or behaviors where activation of TRPM8-expressing cold-sensitive neurons generates to behavioral responses, and inhibitory, where the activation of TRPM8 cells leads to the inhibition of behavioral responses. Active behaviors include responses to innocuous cool, noxious cold, thermoregulation, and cold hypersensitivity after injury. Inhibitory behaviors include inhibition of pain by mild cooling and the inhibition of itch. ❧ The data presented here expand the previously established role of TRPM8 as an in vivo sensor of innocuous cold into a channel involved in a variety of behaviors, including some which are intuitively opposed (i.e. pain and analgesia). Furthermore, we have found a previously unappreciated role for TRPM8 in the inhibition of itch, a finding which will surely create new avenues of drug development for the treatment of chronic itch conditions. Altogether, these studies suggest that the population of sensory neurons expressing TRPM8 is quite diverse, and that understanding this diversity may someday enable us to pharmacologically manipulate specific subsets, leading to novel treatments for various sensory-related pathologies as well as a better understanding of the logic of thermosensation and pain.

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THE ROLES OF TRPM8 IN COLD SENSATION: THE SIX SIDES OF TRPM8
by
Wendy Michelle Knowlton
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
August 2012
Copyright 2012 Wendy Michelle Knowlton